In search of better antidepressants

10:13 December 12, 2012

Anne Trafton, MIT News Office

A new study from researchers at MIT and Stanford University pinpoints brain cells that appear to be critically involved in depression, offering a possible target for new, more effective antidepressants.

By stimulating these cells to deliver dopamine to other parts of the brain, the researchers were able to immediately eliminate symptoms of depression in mice. They also induced depression in normal mice by shutting off the dopamine source.

The findings could help researchers develop antidepressants that are more precisely targeted, says Kay Tye, an assistant professor of brain and cognitive sciences at MIT and one of the lead authors of a paper on the work appearing in the Dec. 12 online edition of Nature.

“The first step to achieving a new era of therapy is identifying targets like these,” says Tye, who is a member of MIT’s Picower Institute for Learning and Memory. “The fact that this target exists, I really hope it motivates drug companies to revitalize their neuroscience research groups.”

Tye performed much of the research as a postdoc in the lab of Stanford professor Karl Deisseroth, the senior author of the paper. Other lead authors are Stanford research assistant Julie Mirzabekov and Stanford postdoc Melissa Warden.

Finding targets

Depression affects an estimated one in 10 Americans, many of whom receive drugs that boost the brain chemical serotonin. However, these drugs (which include Prozac) require four to six weeks to have any effect. This suggests, Tye says, that serotonin may not be part of the brain system most responsible for depression-related symptoms.

“If serotonin was directly underlying the antidepressant effects of Prozac, then the very first day you take Prozac you should feel the effects, because that’s what it’s targeting immediately,” she says. “The fact that it takes so long for the drug to work makes me think that the immediate effect of the drug itself is not having an antidepressant effect. When you have the drug in your system for a long time, the brain adapts, and the adaptation might actually be what is underlying the antidepressant effects of these drugs.”

Finding more specific targets, rather than dousing the whole brain in chemicals, is key to developing better therapies, Tye says.

The researchers decided to investigate the dopamine system because it is known to play a major role in reward, motivation and pleasure. People suffering from depression often lack motivation, so dopamine has been considered a prime suspect in the disease. “Depressed patients will move around less, they have trouble getting out of bed, they don’t enjoy things that they used to enjoy,” Tye says.

Additionally, Parkinson’s disease patients, who suffer from dramatically reduced dopamine levels that severely impair their movements, often experience depression before the complete onset of Parkinson’s symptoms.

Dopamine control

For this study, the researchers used a relatively new technology known as optogenetics to selectively inhibit or stimulate dopamine-releasing neurons in the ventral tegmental area (VTA), which is a primary source of the brain’s dopamine for reward and motivation.

Optogenetics allows scientists to control neurons’ activity by genetically engineering them to express a light-sensitive protein that regulates the flow of ions in and out of the cell. Exposing these neurons to light turns them on or off nearly instantaneously. This offers a much more precise way of manipulating brain circuits than drugs, which can influence neighboring neurons and take more time to exert their effects.

In the first part of the study, the researchers turned off VTA dopamine-releasing neurons in normal mice. This immediately provoked depression-like symptoms, including a decline in motivation and the inability to feel pleasure.

Next, the researchers tested what would happen if they turned on VTA neurons in mice showing symptoms of depression. To generate depressive behavior, these mice were exposed to some type of mild stress twice a day for 10 weeks. Stressors included disruptions in circadian rhythms, social isolation, overcrowding or changes in temperature.

In humans, depression is often induced by similar patterns of low-grade but constant stress, Tye says.

This chronic mild stress is very different from severe acute stress, which can lead to post-traumatic stress disorder, Tye says. “It’s more like a wearing away, where you don’t really feel like you’re in control. You never know what’s going to happen. You just feel helpless as all these frustrating or annoying things happen.”

When the researchers caused the VTA neurons in these mice to fire in bursts, flooding their brains with dopamine, the mice returned to normal behavior patterns within about 10 seconds.

Neurons in the VTA send dopamine to many different parts of the brain, but the researchers found that dopamine signals sent to the nucleus accumbens, known to play roles in reward, pleasure, fear and addiction, appear to have the most important role in controlling depression.

‘A bird’s-eye view’

James Bibb, an associate professor of psychiatry at the University of Texas Southwestern Medical Center, says the new study represents a “tour de force of cutting-edge neuroscience.”

“This gives us a completely new bird’s-eye view of the critical synapses that will need to be targeted to more effectively treat mood disorders,” says Bibb, who was not part of the research team. “Antidepressants represent the largest share of the mental-illness drug market and drug developers may very well use this information to come up with new and greatly needed treatments for those [who] suffer from major depressive disorder.”

In her current research, Tye is looking for more new targets for antidepressants, both in the dopamine circuit studied in this paper and in other parts of the brain. She is also interested in examining how stress experienced early in life can influence health later on.

The research was funded by the Picower Institute Innovation Fund, the JPB Foundation, the Helen Hay Whitney Foundation, the Weigers Family Fund, the National Institute of Mental Health, the National Institute on Drug Abuse, the Defense Advanced Research Projects Agency, the Keck Foundation, the McKnight Foundation, the Gatsby Charitable Foundation, the Snyder Foundation, the Woo Foundation and the Albert Yu and Mary Bechman Foundation.

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